SUMMARY Diabetic nephropathy (DN) is the major cause of end stage renal disease (ESRD) in the United States. Only 20-40% of diabetics get DN and studies support a familial predisposition to DN, and segregation analysis is consistent with a dominant genetic risk for diabetic nephropathy. Like humans, inbred strains of mice exhibit differential susceptibility to diabetic nephropathy, with DBA/2J being susceptible to DN, while C57BL/6J is resistant to DN. Over the past five years, under the auspices of the Animal Models of Diabetic Complications Consortium (AMDCC), our group performed a phenotype driven screen of ethyl-nitrosourea (ENU) mutagenized diabetic C57BL/6J mice to identify new mutations predisposing to diabetic nephropathy (DN). We executed a dominant screen of progeny from mutagenized C57BL/6J males and C57BL/6J Ins2Akita females and ultimately established two mutant lines that convert the DN resistant C57BL/6J strain to a susceptible line, exhibiting progressive albuminuria and renal insufficiency. This trait is heritable and transmitted to ~50% of diabetic progeny as a dominant monogenetic trait. We have now back-crossed these C57BL/6J mice to Balb/C for two generations (N2) and are phenotyping the N2 B6xBalb/C mutant progeny for albuminuria. Association of albuminuria the C57BL/6J chromosomal segments inherited in the backcross with the albuminuria in diabetic Balb/C mice should allow determination of candidate loci within which the ENU mutagenized genes reside. The present proposal has two specific aims: 1) To map the chromosomal interval containing the genes responsible for Nphrp1 and Nphrp2, dominant ENU mutations associated with diabetic albuminuria. 2) To develop models of accelerated diabetic nephropathy using Nphrp1 and Nphrp2 mutants. Through these pilot and feasibility studies we hope to discover novel genetic pathways underlying the path to diabetic nephropathy. NARRATIVE Diabetic kidney disease is the major cause of kidney failure in the U.S., however only 20-40% of diabetics get this disease. There is strong evidence that genetic differences between people underline the reason that some people get renal failure while others don't. This proposal is to use the power of mouse genetics to discover genes that cause kidney failure in diabetes mellitus.